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Background. In the African meningitis belt, Neisseria meningitidis serogroup W135 has emerged as a cause of epidemic disease. The establishment of W135 as the predominant cause of endemic disease has not been described. Methods. We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000-2005. The system was enhanced in 2003 to include clinical data collection of cases from sentinel sites. Isolates were characterized by pulsed field gel electrophoresis and multilocus sequence typing. Results. A total of 2135 cases of invasive meningococcal disease were reported, of which 1113 (52%) occurred in Gauteng Province, South Africa. In this province, rates of disease increased from 0.8 cases per 100,000 persons in 2000 to 4.0 cases per 100,000 persons in 2005; the percentage due to serogroup W135 increased from 7% (4 of 54 cases) to 75% (221 of 295 cases). The median age of patients infected with serogroup W135 was 5 years (interquartile range, 2-23 years), compared with 21 years (range, 8-26 years) for those infected with serogroup A (). The incidence of W135 disease increased in all age groups. Rates were highest among infants (age, <1 year), increasing from 5.1 cases per 100,000 persons in 2003 to 21.5 cases per 100,000 persons in 2005. Overall case-fatality rates doubled, from 11% in 2003 to 22% in 2005. Serogroup W135 was more likely to cause meningococcemia than was serogroup A (82 [28%] of 297 cases vs. 11 [8%] of 141 cases; odds ratio, 8.9, 95% confidence interval, 2.2-36.3). A total of 285 (95%) of 301 serogroup W135 isolates were identified as 1 clone by pulsed-field gel electrophoresis; 7 representative strains belonged to the ST-11/ET-37 complex. Conclusions. Serogroup W135 has become endemic in Gauteng, South Africa, causing disease of greater severity than did the previous predominant serogroup A strain. [ABSTRACT FROM AUTHOR]